The statin class of drugs has been shown to reduce stroke and myocardial infarction in patients with hypercholesterolemia. Intriguingly, the statins have been shown to accomplish this not only by reducing cholesterol levels, but also by improving nitric oxide bioactivity and thereby reversing endothelial dysfunction in human subjects. Atorvastatin is one of the most widely prescribed drugs in the United States, with a well-characterized and very acceptable side effect profile. Our group and others have published evidence that approximately half of patients with sickle cell disease have physiological and biochemical evidence of impaired nitric oxide bioavailability. This appears to contribute to impaired regional blood flow in patients with sickle cell disease, particularly during vaso-occlusive episodes. Therefore, it is attractive to test atorvastatin for its hypothetical ability to restore nitric oxide dependent blood flow in patients with sickle cell disease. We measured forearm blood flow by plethysmography to determine the response to infusion of L-NMMA, a nitric oxide synthase inhibitor, to which sickle cell patients have a blunted response. After four weeks of oral outpatient atorvastatin therapy, this study was repeated, with increased responsiveness to L-NMMA as the primary outcome variable. Atorvastatin-induced alterations in blood flow to acetylcholine and to nitroprusside were also evaluated. Additional secondary studies evaluated the degree to which the elevated level of xanthine oxidase in sickle cell patients inhibits nitric oxide-mediated blood flow;markers of inflammation and oxidation;and gene expression by microarray and pilot studies of proteomics in sickle cell patients. In addition, endothelial progenitor cells (EPC) in circulating blood were researched, which are indicative of vascular health in the general population. As of 28 October 2003, we obtained IRB approval to begin these studies. We began enrollment in March 2004. Subjects with SCD with features of vasculopathy were selectively recruited if they had higher than median plasma levels of soluble VCAM-1, tricuspid regurgitant jet velocity (TRV) greater than or equal to 2.5 meters per second (m/s), or previous demonstration of impaired vasodilatory response to a nitric oxide donor. Twenty-four adult subjects with HbSS and 10 control subjects underwent measurement of baseline EPC levels in peripheral blood. The SCD subjects were then treated with a 4-week course of atorvastatin, with a repeat measurement of circulating EPC levels. TRV was measured by Doppler echocardiography before and after atorvastatin treatment. Patients with SCD (n = 24) had significantly fewer circulating EPCs than African-American control subjects (n = 10) at baseline, (8.9 +/-12.5 vs. 24.7 +/- 31.1 colonies/well, mean SEM, p <0.05). SCD patients with lower than median EPC number (<2.5 colonies/well) had a significantly higher serum alkaline phosphatase level than higher EPC patients (111 +/- 51 vs. 75 +/- 24 units/L, p = 0.03), a previously published independent correlate of pulmonary hypertension. SCD patients with lower EPC number showed a trend towards higher TRV (2.6 +/- 0.3 vs. 2.4 +/- 0.2 m/sec, p = 0.09). In males with SCD, EPC number positively correlated with serum C reactive protein (r = 0.82, n = 11, p = 0.006). Finally, atorvastatin therapy did not increase EPC number in SCD patients from baseline after 2 or 4 weeks of therapy (9.9 +/- 13.9 vs. 5.4 +/- 9.1 vs. 4.9 +/- 7.2 colonies/well, p = 0.46), and it did not change TRV (2.5 +/- 0.1 vs. 2.5+/- 0.1 m/sec). Compared to African-American controls, patients with SCD have much lower circulating EPC number, a new indicator of poor vascular health in these patients. SCD patients with lower EPC number show a pattern of overlap with markers of pulmonary hypertension. These findings are consistent with a role for low EPC number as a marker of or contributor to vascular dysfunction and pulmonary arterial hypertension in patients with SCD, but further study is needed. Lastly, treatment with atorvastatin did not improve EPC number or pulmonary hypertension in a four week course of treatment. This study is now closed to accrual and is open for planned secondary outcome assays of blood specimens and data analysis only.